PROJECT SUMMARY Despite intensive investigation, the factors dictating human longevity and healthy aging continue to remain largely a mystery. The current theory of aging suggests that the balance between two competing influences ? damaging factors that alter cellular function and protective mechanisms that defend against deleterious factors ? is the key determinant of biological aging. The nature of these critical damaging factors and the corresponding protective mechanisms, however, still remain unknown. Recent work has identified reactive electrophiles as well as the enzymes responsible for their detoxification as critical to biological aging. Reactive electrophiles represent small molecule metabolites that are highly reactive with endogenous cellular nucleophiles, including macromolecular targets such as proteins, DNA and lipids, thereby covalently and irreversibly altering target function, signal transduction and cellular integrity. Reactive electrophiles may be derived from either exogenous exposures, such as dietary sources, microbiota, environmental toxins, and drugs, or from endogenous cellular metabolic processes, including lipid peroxidation and other reactions triggered by reactive oxygen species. Accumulating evidence in worms, flies, and lower mammals have associated increased reactive electrophiles with limited lifespan and enhanced electrophile detoxification mechanisms with exceptional longevity. To date, measures of specific reactive electrophiles have been limited and it remains unknown whether specific reactive electrophiles influence biological aging and age-associated diseases in humans. Our laboratory has recently developed novel high throughput mass spectrometry based approaches for selective extraction and measure of reactive electrophiles from human plasma. We have applied these approaches in human populations and have found distinct reactive electrophile compounds in plasma that are highly associated at genome-wide statistical thresholds with progressive chronologic age. In this GEMSSTAR application, the Applicant aims to comprehensively explore the role of reactive electrophiles in human aging. Specifically, proposed studies will determine whether families with exceptional longevity are protected from reactive electrophiles and exhibit electrophile patterns comparable to individuals of a younger biological age as well as whether circulating reactive electrophiles serve as predictors of longevity and healthy aging. The Applicant is an early stage physician-scientist with a track record of dedication to scientific pursuits and discovery. This GEMSSTAR application leverages the Applicant's trans-disciplinary scientific skills with strong institutional support, mentorship, and a comprehensive Professional Development Plan to shed unprecedented insight into the mechanisms of aging while launching the Applicant's long-term independent career in translational aging research.